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nmdar inhibition

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https://www.readbyqxmd.com/read/28432142/structural-similarities-between-neuregulin-1-3-isoforms-determine-their-subcellular-distribution-and-signaling-mode-in-central-neurons
#1
Detlef Vullhorst, Tanveer Ahmad, Irina Karavanova, Carolyn Keating, Andres Buonanno
The Neuregulin (NRG) family of ErbB ligands is comprised of numerous variants originating from the use of different genes, alternative promoters and splice variants. NRGs have generally been thought to be transported to axons and presynaptic terminals where they signal via ErbB3/4 receptors in paracrine or juxtacrine mode. However, we recently demonstrated that unprocessed pro-NRG2 accumulates on cell bodies and proximal dendrites, and that NMDAR activity is required for shedding of its ectodomain by metalloproteinases...
April 21, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28404816/pick1-ca-2-sensor-modulates-nmda-receptor-dependent-microrna-mediated-translational-repression-in-neurons
#2
Dipen Rajgor, Maria Fiuza, Gabrielle T Parkinson, Jonathan G Hanley
miRNAs are important regulators of localized mRNA translation in neuronal dendrites. The presence of RNA-induced silencing complex (RISC) proteins in these compartments and the dynamic miRNA expression changes that occur in response to neuronal stimulation highlights their importance in synaptic plasticity. Previously we demonstrated a novel interaction between the major RISC component Argounaute-2 (Ago2) and the BAR-domain protein PICK1. PICK1 recruits Ago2 to recycling endosomes in dendrites, where it inhibits miRNA-mediated translational repression...
April 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28400714/deletion-of-trpc6-attenuates-nmda-receptor-mediated-ca-2-entry-and-ca-2-induced-neurotoxicity-following-cerebral-ischemia-and-oxygen-glucose-deprivation
#3
Jin Chen, Zhaozhong Li, Jeffery T Hatcher, Qing-Hui Chen, Li Chen, Robert D Wurster, Sic L Chan, Zixi Cheng
Transient receptor potential canonical 6 (TRPC6) channels are permeable to Na(+) and Ca(2+) and are widely expressed in the brain. In this study, the role of TRPC6 was investigated following ischemia/reperfusion (I/R) and oxygen-glucose deprivation (OGD). We found that TRPC6 expression was increased in wild-type (WT) mice cortical neurons following I/R and in primary neurons with OGD, and that deletion of TRPC6 reduced the I/R-induced brain infarct in mice and the OGD- /neurotoxin-induced neuronal death. Using live-cell imaging to examine intracellular Ca(2+) levels ([Ca(2+)] i ), we found that OGD induced a significant higher increase in glutamate-evoked Ca(2+) influx compared to untreated control and such an increase was reduced by TRPC6 deletion...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28356001/atomoxetine-protects-against-nmda-receptor-mediated-hippocampal-neuronal-death-following-transient-global-cerebral-ischemia
#4
Joon Ha Park, Yang Hee Kim, Ji Hyeon Ahn, Soo Young Choi, Seongkweon Hong, Sung Koo Kim, Il Jun Kang, Young-Myeong Kim, Tae-Kyeong Lee, Moo-Ho Won, Choong-Hyun Lee
BACKGROUND: Atomoxetine has been widely used for the treatment of attention-deficit/hyperactivity disorder. ATX has additional abilities such as antagonistic effects on the N-methyl-D-aspartate receptors (NMDARs) and benefit effects in some animal models of neurological disorders. However, there were few studies regarding protective effects and related mechanisms of ATX against cerebral ischemic insults. OBJECTIVE: The objective of this study is to investigate neuroprotection of ATX pretreatment and its mechanisms in the hippocampal cornu ammonis 1 (CA1) region following transient global cerebral ischemia in gerbils...
March 27, 2017: Current Neurovascular Research
https://www.readbyqxmd.com/read/28346482/24s-hydroxycholesterol-and-25-hydroxycholesterol-differentially-impact-hippocampal-neuronal-survival-following-oxygen-glucose-deprivation
#5
Min-Yu Sun, Amanda Taylor, Charles F Zorumski, Steven Mennerick
N-methyl-D-aspartate receptors (NMDARs), a major subtype of glutamate receptor mediating excitatory transmission throughout the CNS, participate in ischemia-induced neuronal death. Unfortunately, undesired side effects have limited the strategy of inhibiting/blocking NMDARs as therapy. Targeting endogenous positive allosteric modulators of NMDAR function may offer a strategy with fewer downsides. Here, we explored whether 24S-hydroxycholesterol (24S-HC), an endogenous positive NMDAR modulator characterized recently by our group, participates in NMDAR-mediated excitotoxicity following oxygen-glucose deprivation (OGD) in primary neuron cultures...
2017: PloS One
https://www.readbyqxmd.com/read/28322273/neuregulin-2-ablation-results-in-dopamine-dysregulation-and-severe-behavioral-phenotypes-relevant-to-psychiatric-disorders
#6
L Yan, A Shamir, M Skirzewski, E Leiva-Salcedo, O B Kwon, I Karavanova, D Paredes, O Malkesman, K R Bailey, D Vullhorst, J N Crawley, A Buonanno
Numerous genetic and functional studies implicate variants of Neuregulin-1 (NRG1) and its neuronal receptor ErbB4 in schizophrenia and many of its endophenotypes. Although the neurophysiological and behavioral phenotypes of NRG1 mutant mice have been investigated extensively, practically nothing is known about the function of NRG2, the closest NRG1 homolog. We found that NRG2 expression in the adult rodent brain does not overlap with NRG1 and is more extensive than originally reported, including expression in the striatum and medial prefrontal cortex (mPFC), and therefore generated NRG2 knockout mice (KO) to study its function...
March 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28321180/multiple-kinases-involved-in-the-nicotinic-modulation-of-gamma-oscillations-in-the-rat-hippocampal-ca3-area
#7
JianGang Wang, XiaoLong He, Fangli Guo, XiangLin Cheng, Yali Wang, XiaoFang Wang, ZhiWei Feng, Martin Vreugdenhil, ChengBiao Lu
Neuronal synchronization at gamma band frequency (20-80 Hz, γ oscillations) is closely associated with higher brain function, such as learning, memory and attention. Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the hippocampus, and modulate hippocampal γ oscillations, but the intracellular mechanism underlying such modulation remains elusive. We explored multiple kinases by which nicotine can modulate γ oscillations induced by kainate in rat hippocampal area CA3 in vitro. We found that inhibitors of cyclic AMP dependent kinase (protein kinase A, PKA), protein kinase C (PKC), N-methyl-D-aspartate receptor (NMDA) receptors, Phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinases (ERK), each individually could prevent the γ oscillation-enhancing effect of 1 μM nicotine, whereas none of them affected baseline γ oscillation strength...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28315524/a-cellular-mechanism-for-inverse-effectiveness-in-multisensory-integration
#8
Torrey Ls Truszkowski, Oscar A Carrillo, Julia Bleier, Carolina M Ramirez-Vizcarrondo, Daniel L Felch, Molly McQuillan, Christopher P Truszkowski, Arseny S Khakhalin, Carlos D Aizenman
To build a coherent view of the external world, an organism needs to integrate multiple types of sensory information from different sources, a process known as multisensory integration (MSI). Previously, we showed that the temporal dependence of MSI in the optic tectum of Xenopus laevis tadpoles is mediated by the network dynamics of the recruitment of local inhibition by sensory input (Felch et al., 2016). This was one of the first cellular-level mechanisms described for MSI. Here, we expand this cellular level view of MSI by focusing on the principle of inverse effectiveness, another central feature of MSI stating that the amount of multisensory enhancement observed inversely depends on the size of unisensory responses...
March 18, 2017: ELife
https://www.readbyqxmd.com/read/28303894/an-excessive-increase-in-glutamate-contributes-to-glucose-toxicity-in-%C3%AE-cells-via-activation-of-pancreatic-nmda-receptors-in-rodent-diabetes
#9
Xiao-Ting Huang, Chen Li, Xiang-Ping Peng, Jia Guo, Shao-Jie Yue, Wei Liu, Fei-Yan Zhao, Jian-Zhong Han, Yan-Hong Huang, Yang-Li, Qing-Mei Cheng, Zhi-Guang Zhou, Chen Chen, Dan-Dan Feng, Zi-Qiang Luo
In the nervous system, excessive activation of NMDA receptors causes neuronal injury. Although activation of NMDARs has been proposed to contribute to the progress of diabetes, little is known about the effect of excessive long-term activation of NMDARs on β-cells, especially under the challenge of hyperglycemia. Here we thoroughly investigated whether endogenous glutamate aggravated β-cell dysfunction under chronic exposure to high-glucose via activation of NMDARs. The glutamate level was increased in plasma of diabetic mice or patients and in the supernatant of β-cell lines after treatment with high-glucose for 72 h...
March 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28293172/ethanol-modulates-the-spontaneous-complex-spike-waveform-of-cerebellar-purkinje-cells-recorded-in-vivo-in-mice
#10
Guang-Jian Zhang, Mao-Cheng Wu, Jin-Di Shi, Yin-Hua Xu, Chun-Ping Chu, Song-Biao Cui, De-Lai Qiu
Cerebellar Purkinje cells (PCs) are sensitive to ethanol, but the effect of ethanol on spontaneous complex spike (CS) activity in these cells in vivo is currently unknown. Here, we investigated the effect of ethanol on spontaneous CS activity in PCs in urethane-anesthetized mice using in vivo patch-clamp recordings and pharmacological manipulation. Ethanol (300 mM) induced a decrease in the CS-evoked pause in simple spike (SS) firing and in the amplitude of the afterhyperpolarization (AHP) under current clamp conditions...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28285942/small-molecule-inhibitors-of-psd95-nnos-protein-protein-interactions-suppress-formalin-evoked-fos-protein-expression-and-nociceptive-behavior-in-rats
#11
Lawrence M Carey, Wan-Hung Lee, Tannia Gutierrez, Pushkar M Kulkarni, Ganesh A Thakur, Yvonne Y Lai, Andrea G Hohmann
Excessive activation of NMDA receptor (NMDAR) signaling within the spinal dorsal horn contributes to central sensitization and the induction and maintenance of pathological pain states. However, direct antagonism of NMDARs produces undesirable side effects which limit their clinical use. NMDAR activation produces central sensitization, in part, by initiating a signaling cascade that activates the enzyme neuronal nitric oxide synthase (nNOS) and generates the signaling molecule nitric oxide. NMDAR-mediated activation of nNOS requires a scaffolding protein, postsynaptic density protein 95kDa (PSD95), which tethers nNOS to NMDARs...
May 4, 2017: Neuroscience
https://www.readbyqxmd.com/read/28283345/cystathionine-%C3%AE-synthase-derived-hydrogen-sulfide-is-required-for-amygdalar-long-term-potentiation-and-cued-fear-memory-in-rats
#12
Hai-Bo Chen, Wen-Ning Wu, Wei Wang, Xun-Hu Gu, Bin Yu, Bo Wei, Yuan-Jian Yang
Hydrogen sulfide (H2S) is an endogenous gaseous molecule that functions as a neuromodulator in the brain. We previously reported that H2S regulated amygdalar synaptic plasticity and cued fear memory in rats. However, whether endogenous H2S is required for amygdalar long-term potentiation (LTP) induction and cued fear memory formation remains unclear. Here, we show that cystathionine-β-synthase (CBS), the predominant H2S-producing enzyme in the brain, was highly expressed in the amygdala of rats. Suppressing CBS activity by inhibitor prevented activity-triggered generation of H2S in the lateral amygdala (LA) region...
March 8, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28277064/inhibition-of-nmda-receptor-function-with-an-anti-glun1-s2-antibody-impairs-human-platelet-function-and-thrombosis
#13
Taryn N Green, Justin R Hamilton, Marie-Christine Morel-Kopp, Zhaohua Zheng, Ting-Yu T Chen, James I Hearn, Peng P Sun, Jack U Flanagan, Deborah Young, P Alan Barber, Matthew J During, Christopher M Ward, Maggie L Kalev-Zylinska
GluN1 is a mandatory component of N-methyl-D-aspartate receptors (NMDARs) best known for their roles in the brain, but with increasing evidence for relevance in peripheral tissues, including platelets. Certain anti-GluN1 antibodies reduce brain infarcts in rodent models of ischaemic stroke. There is also evidence that human anti-GluN1 autoantibodies reduce neuronal damage in stroke patients, but the underlying mechanism is unclear. This study investigated whether anti-GluN1-mediated neuroprotection involves inhibition of platelet function...
February 21, 2017: Platelets
https://www.readbyqxmd.com/read/28270746/effects-of-repeated-ethanol-exposures-on-nmda-receptor-expression-and-locomotor-sensitization-in-mice-expressing-ethanol-resistant-nmda-receptors
#14
Carolina R den Hartog, Meghin Gilstrap, Bethany Eaton, Daniel H Lench, Patrick J Mulholland, Gregg E Homanics, John J Woodward
Evidence from a large number of preclinical studies suggests that chronic exposure to drugs of abuse, such as psychostimulants or ethanol induces changes in glutamatergic transmission in key brain areas associated with reward and control of behavior. These changes include alterations in the expression of ionotropic glutamate receptors including N-methyl-D-aspartate receptors (NMDAR) that are important for regulating neuronal activity and synaptic plasticity. NMDA receptors are inhibited by ethanol and reductions in NMDA-mediated signaling are thought to trigger homestatic responses that limit ethanol's effects on glutamatergic transmission...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28269783/modulating-the-balance-of-synaptic-and-extrasynaptic-nmda-receptors-shows-positive-effects-against-amyloid-%C3%AE-induced-neurotoxicity
#15
Yan Huang, Wei Shen, Jie Su, Bin Cheng, Dong Li, Gang Liu, Wen-Xia Zhou, Yong-Xiang Zhang
Alzheimer's disease (AD) patients suffer a disturbance in the balance between synaptic (GluN2A, mediating the protective pathway) and extrasynaptic NMDA receptors (NMDARs) (GluN2B, mediating the excitotoxic pathway), and, therefore, restoring the balance of GluN2A and GluN2B should be beneficial for AD. In this study, the GluN2B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effect on amyloid-β (Aβ)-induced long-term potentiation deficits. Enhancing the activity of GluN2A had a protective effect against Aβ, and specific activation of GluN2A and inhibition of GluN2B showed a better protective effect...
March 2, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28244984/schizophrenia-like-phenotypes-in-mice-with-nmda-receptor-ablation-in-intralaminar-thalamic-nucleus-cells-and-gene-therapy-based-reversal-in-adults
#16
K Yasuda, Y Hayashi, T Yoshida, M Kashiwagi, N Nakagawa, T Michikawa, M Tanaka, R Ando, A Huang, T Hosoya, T J McHugh, M Kuwahara, S Itohara
In understanding the mechanism of schizophrenia pathogenesis, a significant finding is that drug abuse of phencyclidine or its analog ketamine causes symptoms similar to schizophrenia. Such drug effects are triggered even by administration at post-adolescent stages. Both drugs are N-methyl-d-aspartate receptor (NMDAR) antagonists, leading to a major hypothesis that glutamate hypofunction underlies schizophrenia pathogenesis. The precise region that depends on NMDAR function, however, is unclear. Here, we developed a mouse strain in which NMDARs in the intralaminar thalamic nuclei (ILN) were selectively disrupted...
February 28, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28240305/increased-pkc-activity-and-altered-gsk3%C3%AE-nmdar-function-drive-behavior-cycling-in-hint1-deficient-mice-bipolarity-or-opposing-forces
#17
Javier Garzón-Niño, María Rodríguez-Muñoz, Elsa Cortés-Montero, Pilar Sánchez-Blázquez
Mice with histidine triad nucleotide-binding protein 1 (HINT1) deletion exhibit manic-like symptoms that evolve into depressive-like behavior in response to stressful paradigms. Molecular and electrophysiological studies have indicated that HINT1(-/-) mice exhibit increased PKC, PKA, and GSK3β activities, as well as glutamate N-methyl-D-aspartate receptor (NMDAR)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and NR2B/NR2A subunit ratios. Pharmacological interventions stabilized their behavior but through different mechanisms...
February 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28225161/treatment-of-experimental-status-epilepticus-with-synergistic-drug-combinations
#18
Jerome Niquet, Roger Baldwin, Lucie Suchomelova, Lucille Lumley, Roland Eavey, Claude G Wasterlain
During status epilepticus (SE), synaptic γ-aminobutyric acid A receptors (GABAA Rs) become internalized and inactive, whereas spare N-methyl-d-aspartate receptors (NMDARs) assemble, move to the membrane, and become synaptically active. When treatment of SE is delayed, the number of synaptic GABAA Rs is drastically reduced, and a GABAA agonist cannot fully restore inhibition. We used a combination of low-dose diazepam (to stimulate the remaining GABAA Rs), ketamine (to mitigate the effect of the NMDAR increase), and valproate (to enhance inhibition at a nonbenzodiazepine site) to treat seizures in a model of severe cholinergic SE...
April 2017: Epilepsia
https://www.readbyqxmd.com/read/28206646/acute-melamine-affects-spatial-memory-consolidation-via-inhibiting-hippocampal-nmdar-dependent-ltd-in-rats
#19
Lei An, Wei Sun
No abstract text is available yet for this article.
February 16, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28202503/vitamin-d-and-depression-cellular-and-regulatory-mechanisms
#20
REVIEW
Michael J Berridge
Depression is caused by a change in neural activity resulting from an increase in glutamate that drives excitatory neurons and may be responsible for the decline in the activity and number of the GABAergic inhibitory neurons. This imbalance between the excitatory and inhibitory neurons may contribute to the onset of depression. At the cellular level there is an increase in the concentration of intracellular Ca(2+) within the inhibitory neurons that is driven by an increase in entry through the NMDA receptors (NMDARs) and through activation of the phosphoinositide signaling pathway that generates inositol trisphosphate (InsP3) that releases Ca(2+) from the internal stores...
April 2017: Pharmacological Reviews
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